Neuropeptides

Neuropeptides are generally thought to modulate the effects of classical neurotransmitters and are often collocated with neurotransmitters within neurons. This section focuses on six neuropeptides that have been implicated in the pathophysiology of psychiatric disorders.

Corticotropin-Releasing Factor

Corticotropin-releasing factor (CRF) is best known as a hormone that is secreted by the hypothalamus and that stimulates adrenocorticotropic hormone (ACTH) release from the pituitary, which results in the production of cortisol by the adrenal glands. Specifically, CRF is localized to neurons of the paraventricular nucleus in the hypothalamus, which send axons to the median eminence. CRF-containing cells are also localized to other hypothalamic nuclei, such as the medial preoptic area and the dorsomedial, arcuate, and mammillary nuclei (DeSouza and Grigoriadis 2002), as well as to the amygdala and bed nucleus of the stria terminalis (Keller et al. 2006). Besides the median eminence, CRF axons are present in the cerebral cortex, brain stem (including the locus coeruleus), and spinal cord. To date, two CRF receptors have been identified, CRF1 and CRF2. CRF1 receptors are expressed in the pituitary, cerebral cortex, hippocampus, amygdala, and medial septum, and CRF2 receptors are localized to the hypothalamic nuclei, lateral septum, and bed nucleus of the stria terminalis (Keller et al. 2006).

It has been hypothesized that hyperactivity of hypothalamic CRF might underlie the hypercortisolemia and contribute to the symptomatology seen in major depression (Aborelius et al. 1999). Furthermore, given that both NE and DA have been shown to be involved with stress as well as with depression, the presence of CRF-containing axons in NE- and DA-containing nuclei provides another mechanism by which CRF can affect stress responses (Austin et al. 1997).

CRF also appears to have effects on cognitive processing. Of interest, CRF is found in GABA-containing cells in the cerebral cortex, with the highest densities of these cells found in prefrontal, insular, and cingulate cortices (DeSouza and Grigoriadis 2002). In addition, cortical CRF has also been implicated in major depression and in Alzheimer's disease. For example, a decrease in CRF binding sites in the frontal cortex of suicide victims compared with normal controls has been demonstrated (Mitchell 1998). Furthermore, in postmortem tissue from individuals with Alzheimer's disease, CRF-containing axons are associated with amyloid deposits in the cerebral cortex (Powers et al. 1987); reduced CRF levels in frontal, temporal, and parietal cortices are correlated with the severity of dementia (Davis et al. 1999).

Neuropeptide Y

Neuropeptide Y (NPY) is a 36-amino acid peptide that, along with its receptors, is widely distributed within the central nervous system (Wettstein et al. 1995). The regions of the human brain that contain high densities of NPY-containing neurons include the striatum and amygdala, with the hypothalamus, cerebral cortex, hippocampus, periaqueductal gray, and basal forebrain having moderate levels of NPY-containing cells (Schwartzberg et al. 1990). Five G

protein-coupled NPY receptor subtypes, termed Y1-Y5, have been identified and cloned (Redrobe et al. 2002). The NPY receptors Y1 and Y2 are the most abundant and are found in the cerebral cortex, thalamus, brain stem, and hypothalamus (Redrobe et al. 2002). In addition to its role in regulating eating behavior, NPY has been implicated in affective disorders. For example, in a rodent model of depression, chronic antidepressant treatment increased NPY and Y1 mRNA levels (Caberlotto et al. 1998). In humans, cerebrospinal fluid and plasma levels of NPY are lower in depressed patients than in controls (Nilsson et al. 1996; Westrin et al. 1999), and these levels increase after electroconvulsive therapy (Mathe et al. 1996). In addition, NPY mRNA is reduced in the prefrontal cortex of subjects with bipolar disorder (Caberlotto and Hurd 2001) and subjects with schizophrenia (Hashimoto et al. 2008).

Substance P

Substance P is a member of the family of neuropeptides known as the tachykinins, which also includes neurokinin A and B. The actions of these neuropeptides are mediated through the specific G protein-coupled receptors NK1, NK2, and NK3, and substance P is the preferred agonist for the NK1 receptor (Hokfelt et al. 2001). Substance P is found throughout the nervous system. In particular, substance P is expressed in brain regions that appear to be involved in emotion, such as the amygdala, periaqueductal gray, and hypothalamus (Pioro et al. 1990). In addition, substance P is collocated with serotonin in approximately 50% of the dorsal raphe neurons in the human brain (Baker et al. 1991; Sergeyev et al. 1999), and a large number of serotonin-containing dorsal raphe neurons express the NK1 receptor (Lacoste et al. 2006).

Studies in animals have suggested that substance P, besides having a role in pain and inflammation, may also be involved in anxiety and in neurochemical responses to stress. For example, injection of substance P into periaqueductal gray matter produced anxiety-like behavior in rats (Aguiar and Brandao

1996). Furthermore, in guinea pigs subjected to maternal separation, the number of neurons with NK1 receptor internalization increased in the basolateral amygdala (Kramer et al. 1998).

Substance P also appears to be involved in depression. For example, elevated concentrations of substance P have been reported in the cerebrospinal fluid of depressed patients (Rimon et al. 2002).

Neurotensin

Neurotensin is a tridecapeptide found throughout the brain, with high tissue concentrations in the amygdala, lateral septum, bed nucleus of the stria terminalis, substantia nigra, and ventral tegmental area (Caceda et al. 2006). Similarly, neurotensin-immunoreactive neurons are found in the amygdala, bed nucleus of the stria terminalis, lateral septum, and preoptic and lateral hypothalamus (Geisler et al. 2006). Three types of neurotensin receptors have been cloned, NTS1-NTS3, with NTS1 and NTS2 being G protein-coupled receptors and NTS3 belonging to the vacuolar sorting receptor family (Caceda et al. 2006). High levels of mRNA for all three of these receptor types are found in the substantia nigra and amygdala.

Neurotensin has a strong association with the dopaminergic system, as evidenced by the heavy neurotensin innervation of nuclei that have high densities of DA cells or axons, such as the ventral tegmental area and the amygdala, respectively (Geisler et al. 2006). In addition, the majority of DA neurons in the ventral tegmental area express NTS1 (Fassio et al. 2000), and neurotensin axons in this area arise from the preoptic and lateral hypothalamus (Zahm et al. 2001). Because of the role of DA in neuropsychiatric disorders such as schizophrenia, the localization and function of neurotensin in the brain have been widely studied. One of the most consistent findings is reduced cerebrospinal fluid concentrations of neurotensin in neuroleptic-naive people diagnosed with schizophrenia (Sharma et al. 1997). In addition, clinically effective antipsychotic drug treatment may increase cerebrospinal fluid neurotensin levels in schizophrenia (Sharma et al. 1997). Neurotensin has also been implicated in Parkinson's disease, which involves the progressive loss of DA neurons in the striatum. For example, decreases in neurotensin receptor binding as well as in NTS1 receptor mRNA have been found in the substantia nigra and striatum of patients with Parkinson's disease (Yamada et al. 1995).

Somatostatin

The neuropeptide somatostatin was first identified in the hypothalamus as a tetradecapeptide (Brazeau et al. 1973). Other peptides of the somatostatin family, all of which are derived from the prosomatostatin protein, include somatostatin-28 and somatostatin-281-12 (Benoit et al. 1982). The hypothalamus and limbic regions such as the amygdala and hippocampus have large numbers of somatostatin-containing neurons. A small number of somatostatin neurons are localized to the cerebral cortex and are particularly abundant in layers 2-3 and layers 5-6 (Epelbaum et al. 1994). Somatostatin-containing neurons in the cerebral cortex have a nonpyramidal morphology and contain GABA (Hendry et al. 1984). The principal somatostatinergic tract projects from the anterior periventricular nucleus of the hypothalamus to the median eminence (Patel 1999). This projection inhibits secretion of growth hormone, thyroid-stimulating hormone, and prolactin from the adenohypophysis (Epelbaum et al. 1994). The actions of somatostatin are mediated by five distinct subtypes of G proteincoupled receptors, SST1-SST5. The SST2 receptor undergoes alternative splicing that results in two forms, SST2A and SST2B (Epelbaum et al. 1994). Although all somatostatin receptors appear to be present in the brain (Patel 1999), the SST2 receptor is the most widely studied. In rodent brain, the SST2A receptor protein has been localized to the cerebral cortex, basal ganglia, and hippocampus (Dournaud et al. 1996; Hervieu and Emson 1998).

The widespread distribution of somatostatin cells and receptors reflects the varied physiological actions that somatostatin release has in the nervous system, ranging from thermoregulation to cognitive functions such as learning and memory (Epelbaum et al. 1994). Deficits in the somatostatin system in Alzheimer's disease are some of the most consistent findings in this neurodegenerative disease. Decreases in cerebrospinal fluid somatostatin levels, selective degeneration of cortical somatostatin neurons, and reduction in cortical somatostatin receptors have all been found in Alzheimer's disease (Bissette

Somatostatin has also been implicated in the pathophysiology of schizophrenia. For example, studies have revealed decreased expression of somatostatin mRNA in the prefrontal cortex of individuals with schizophrenia (Hashimoto et al. 2008), specifically in layers 2-6 (Morris et al. 2008).

Orexins

The orexin neuropeptides, orexin A and orexin B (also known as hypocretin A and hypocretin B), were identified in the late 1990s as endogenous ligands for two orphan G protein-coupled receptors (de Lecea et al. 1998; Sakurai et al. 1998). Orexin A and orexin B are derived from a single precursor gene, prepro-orexin. Because neurons in the lateral hypothalamic area, a region with an established role in feeding behavior, produce these neuropeptides, Sakurai et al. (1998) named them orexins, based on the Greek word for appetite, orexis. Neurons producing orexin are also located in posterior and perifornical hypothalamus. Estimates of the number of orexin neurons range from 3,000 in rat brain (Nambu et al. 1999) to 7,000 in human brain (Peyron et al. 1998). Orexin neurons project throughout the brain, with the exception of the cerebellum (Figure 4-11). Interestingly, orexin neurons project to most of the monoaminergic (substantia nigra, locus coeruleus, dorsal raphe) and cholinergic (medial septum, pedunculopontine, laterodorsal tegmental) nuclei (Sakurai 2007). Orexin neurons also have widespread projections throughout the cerebral cortex. Areas containing high densities of orexin axons include the paraventricular thalamic nucleus, the arcuate nucleus of the hypothalamus, the locus coeruleus, and the dorsal raphe nucleus (Nambu et al. 1999).

FIGURE 4-11. Projections of orexin-containing neurons in the human brain.

The multiple actions of orexin are mediated by two types of G protein-coupled receptors, orexin i and orexin 2, which display high homology. In concert with the widespread projections of orexin neurons, the orexin receptors are located throughout the brain (Marcus et al. 200i). For example, the mRNA for orexin i is found in the prefrontal cortex, the CA2 field of the hippocampus, the paraventricular thalamic nucleus, the ventromedial hypothalamic nucleus, and the locus coeruleus. The distribution of the mRNA for orexin 2 is somewhat complementary to that of orexin i in that it is found in the piriform cortex, CA3 field of the hippocampus, rhomboid thalamic nucleus, dorsomedial hypothalamic nucleus, and tuberomammillary nucleus (Marcus et al. 200i). Some regions of the brain, such as the raphe nuclei, ventral tegmental area, and substantia nigra, express both orexin receptors.

The location of orexin-containing neurons in the feeding center of the brain (lateral hypothalamic area) and the projections of orexin neurons to neuronal systems involved in sleep and wakefulness (locus coeruleus, raphe nuclei, and laterodorsal/pedunculopontine tegmental nuclei) and reward (ventral tegmental area) illustrate the variety of functions in which orexin neurons participate (Harris and Aston-Jones 2006). Supporting orexin's involvement in feeding behavior, administration of an anti-orexin antibody or an orexin i receptor antagonist to rats reduces food intake (Haynes et al. 2002; Yamada et al. 2000). Numerous studies in both animals and humans show that orexin deficiency is the main cause of narcolepsy. For example, mice that lack the orexin gene exhibit physiological symptoms similar to those of human narcolepsy (Chemelli et al. i999). More direct evidence of orexin's role in narcolepsy is that postmortem examination of the brains of narcolepsy patients revealed an 85%-95% reduction in the number of orexin-immunoreactive neurons (Thannickal et al. 2000). A recent study of an orexin receptor antagonist demonstrated the usefulness of this drug in inducing sleep without cataplexy (Brisbare-Roch et al. 2007), providing hope to people who suffer from sleeping disorders like narcolepsy. Current treatments for narcolepsy include addictive amphetamine-like drugs, but patients taking these drugs rarely become addicted (Harris and Aston-Jones 2006). This finding has led to speculation that orexins may also be involved in reward processing and addiction. For example, orexin neurons activate ventral tegmental DA neurons, which, through their projections to the nucleus accumbens, form the "reward" pathway. In addition, in rodents, administration of orexin directly into the ventral tegmental area reinstates an extinguished drug preference (Harris et al. 2005).

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